Head and neck cancer
Expression of stem cell markers Oct3/4 and Nanog and its clinical significance in oral tongue squamous cell carcinoma
- Author(s)：
- Noboru Habu1,2,3, Yorihisa Imanisi1, Koji Sakamoto4, Seiji Shigetomi5, Kuninori Otsuka6, Yoichiro Sato1, Yoshihiro Watanabe1, Kaoru Ogawa1,Yutaka Tokumaru7, Masato Fujii2.
- Affiliation(s)：
- 1. Department of Otorhinolaryngology-Head and Neck Surgery, Keio University School of Medicine
2. National Institute of Sensory Organs, National Tokyo Medical Center
3. Department of Otorhinolaryngology, Tachikawa Hospital.
4. Department of Otorhinolaryngology, Saiseikai Utsunomiya Hospital
5. Department of Otorhinolaryngology, Kawasaki Municipal Hospital
6. Department of Otorhinolaryngology, Saiseikai Yokohamashi Tobu Hospital
7. Department of Otorhinolaryngology, National Tokyo Medical Center
Background: Oral tongue squamous cell carcinoma (TSCC) is known to show high incidence of regional metastasis. Even in the patients with clinical stage I/II (T1-2N0M0) TSCC, delayed neck metastasis (DNM) eventually develops in 20 to 50% of those patients within 2 years, which results in much worse survival as compared to those without DNM. Because the common criteria for elective neck dissection based on dependable prediction of DNM have not been established yet, it is indispensable to elucidate reliable markers predictive of DNM. Recently cancer stem cells (CSCs), a small subpopulation of cancer cells that exhibit self-renewal capacity and pluripotncy, have been proposed to be responsible for carcinogenesis, therapy resistance, relapse and metastasis. The side population (SP) of cancer cells, isolated by a flow cytometry using Hoechst 33342, has been known as CSC rich population in several cancers. However, stemness phenotype of SP in TSCC and its relevance to clinicopathological features remain largely unknown.
Purpose: The present study aimed to determine the reliable CSC markers in TSCC cells and to elucidate the phenotypic difference in cellular behavior between SP and main population (MP). We also aimed to clarify the association of DNM in stage I/II TSCC with the expression of CSC-molecular markers, as well as clinicopathologic factors.
Design: Flow cytometric analysis was applied to isolate SP excluding Hoechst 33342 from MP in established TSCC cell lines (HSC4, SAS and SCC4). Differences in expressions of several CSC markers between SP and MP were examined by semi-quantitative RT-PCR and immunocytochemistry. in vitro proliferation, migration and invasion assays were performed to evaluate each of phenotypic differences between SP and MP. Furthermore, clinicopathological factors and immunohistochemical staining of the selected CSC markers were evaluated using surgical specimens of 50 stage I/II TSCC patients who underwent partial glossectomy alone at the Department of Otorhinolaryngology-Head and Neck Surgery, Keio University Hospital from 1996 to 2009, to statistically analyze the association between those factors/markers and DNM.
Results: Flow cytometric analysis confirmed the presence of SP in all three cell lines. Expression levels of certain CSC markers, particularly Oct3/4 and Nanog, were higher in SP cells than in MP cells. Cell migration and invasion abilities were higher in SP cells than in MP cells, whereas no difference was shown in proliferation ability between SP cells and MP cells. Clinicopathological and immunohistochemical analyses revealed that Oct3/4 expression (p=0.001), Nanog expression (p=0.001), vascular invasion (p=0.009), Mode of invasion (3, 4 vs 1, 2) (p=0.036) and muscular invasion (p=0.010) were significantly correlated with development of DNM in univariate analysis. Multivariate analysis revealed that Oct3/4 expressions (risk ratio=14.78, p=0.002) and vascular invasion (risk ratio=12.93, p=0.017) were independent predictors of DNM in this cohort.
Conclusion: These results suggest that Oct3/4 and Nanog may represent reliable CSC makers in TSCC, and that expression of these molecules may contribute to development of DNM by promoting motility and invasiveness of cancer cells. Furthermore, the patients with stage I/II TSCC that show Oct3/4 expression and vascular invasion in their primary tumors should be considered to be a high risk group of DNM.
Chemoradiotherapy for oropharyngeal cancer: retrospective observational study
by multi-institution
- Author(s)：
- Satoshi Kano, M.D., PhD.1, Akihiro Homma, M.D., PhD.1, Ryuichi Hayashi, M.D.2, Kazuyoshi Kawabata, M.D., PhD.3, Kunitoshi Yoshino, M.D., PhD.4, Shigemichi Iwae, M.D., PhD.5, Yasuhisa Hasegawa, M.D., PhD.6, Kenichi Nibu, M.D. PhD.7, Takakuni Kato, M.D., PhD.8, Kiyoto Shiga, M.D., PhD.9, Kazuto Matsuura, M.D., PhD.10, Nobuya Monden, M.D., PhD.11, Masato Fujii, M.D., PhD.12
- Affiliation(s)：
- 1 Department of Otolaryngology-Head and Neck Surgery, Hokkaido University Graduate School of Medicine, Sapporo, Japan
2 Division of Head and Neck Surgery, National Cancer Center Hospital East, Kashiwa, Japan
3 Department of Head and Neck Oncology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
4 Department of Otolaryngology, Head and Neck Surgery, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan
5 Department of Head and Neck Surgery, Hyogo Cancer Center, Akashi, Japan
6 Department of Head and Neck Surgery, Aichi Cancer Center, Nagoya, Japan
7 Department of Otolaryngology-Head and Neck Surgery, Kobe University Graduate School of Medicine, Kobe, Japan
8 Department of Oto-Rhino-Laryngology, Jikei University School of Medicine, Tokyo, Japan
9 Department of Otolaryngology-Head and Neck Surgery, Tohoku University School of Medicine, Sendai, Japan
10 Division of Head and Neck Surgery, Miyagi Cancer Center, Sendai, Japan
11 Department of Otorhinolaryngology-Head and Neck Surgery, National Shikoku Cancer Center, Matsuyama, Japan
12 Department of Otorhinolaryngology, National Tokyo Medical Center, Tokyo, Japan
Objective. In recent years, the initial treatment strategy for advanced head and neck cancer has shifted from surgery toward chemoradiotherapy. This paradigm shift is particularly marked for oropharyngeal cancer (OPC), because OPC has high sensitivity to radiation and chemotherapy, and the extended resection of the oropharynx directly leads to swallowing and speech disorders. The current study aimed to compare the therapeutic outcomes of surgery with those of concurrent chemoradiotherapy (CCRT) for patients with advanced OPC, and to assess the role of salvage surgery for failure cases undergoing initial CRT.
Methods. The data for 523 patients with previously untreated OPC were obtained from 12 institutions belonging to the Head and Neck Cancer Study Group in Japan Clinical Oncology Group from April 2005 to March 2007. Of the 523 patients, 248 patients were included on the basis of the following criteria: (1) histological proof of squamous cell carcinoma; (2) clinical stage III or IV disease; (3) disease stage other than T4b; (4) no distant metastasis; (5) lateral or anterior wall cancer; and (6) surgery or CCRT as curative treatment. To adjust for baseline differences between the two groups of patients who underwent surgery or CCRT, we performed a matched-pair analysis using propensity scores. We matched a group of patients who underwent surgery with a second group treated with CCRT according to age, gender, subsite, and T and N classification, and analyzed the progression-free survival, local control and swallowing function. Furthermore, we analyzed the treatment local failures, salvage surgeries and survival rates of patients treated with CCRT.
Results. The final matched-pair analysis included 186 patients. The 5-year progression-free survival and local control rates were 51.0% and 54.4% (P = 0.531), and 75.2% and 80.3% (P = 0.399), respectively, in patients treated with surgery and those treated with CCRT. There were no significant differences in all, however the progression-free survival rate in the CRT group seemed to be better than that in the surgery group in T3-4 tumor. Swallowing function in patients treated with CCRT was significantly better than that in patients treated with surgery (P = 0.015). On the other hand, of the 170 patients who received CCRT, 35 patients (21%) had local recurrence or residual disease. Only 11 patients underwent further salvage surgery, and 24 patients received nonsurgical treatment. There were statistically significant differences between two groups in terms of patient age and the presence of a simultaneous regional recurrence. The 5-year overall survival rates for the patients who underwent salvage surgery were 49.1%, whereas those for the patients who received nonsurgical treatment were 16.3%.
Conclusion. CCRT is as effective as surgery in the treatment of OPC and swallowing function was significantly better in the CCRT group compared to patients treated with surgery. However, salvage surgery for OPC was indicated in a limited number of patients with local failure and the survival rate of these patients was not as high as expected. The initial treatment method for OPC should be decided carefully and the limitations of salvage surgery should be fully considered.
